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2,928,837 TETRROPYRIDO,1,5-BENZODIAZEPINE- 2-(3)-GNE Rolf Kallischnigg, Hamburg, Germany, assignor to Chemischc Fabrik Promonta G.rn.b.I-I., Hamburg, Germany, a firm of Germany No Drawing. Application August 27, 1957 Serial No. 680,617

Claims priority, application Germany August 29, 1956 9 Claims. (Cl. 260-296) This invention relates to new diazepine derivatives and a method for preparing the same.

The term diazepine for unsaturated seven-membered rings including two nitrogen atoms, corresponds to the conventional nomenclature used for example in the Chemical Abstracts. The basic compound of the products here in question is described in the Chemical Abstracts, volume 36 (1942), column 4115, Section 6 (W. A. Sexton, J. Chem. Soc. 1942, pages 303-304) as compound (IV) and is listed in the Subject Index of said volume 36 of the Chemical Abstracts as 1,5-benzodiazepine-2-(3)-one on page 7843 in the middle column where 2,928,837 Patented Mar. 15, 1960 It has been found that this condensation can be carried out in inert organic solvents with the evolution of heat. It is preferred to carry out condensation in boiling xylene.

The following examples illustrate some embodiments of and some best modes for carrying out the invention, to which the invention is not limited.

EXAMPLE 1 3,4 [3'4' (1 methyl 12'5'6' ietrahydropyrid0)]- 1 ,5 -benz0diazepine-(3 -2 -one Into a 2-liter distilling flask or apparatus provided with a dropping funnel 88 grams of ortho-phenylene diamine and 1 liter of dry xylene are introduced and the solution is heated to such an extent that the xylene slowly distills over. Into said apparatusduring 5 to 6 hours130 grams of 1-methylpiperidone-4-carboxylic acid-S-ethyl ester in 2 liters of xylene are dropwise added in such a manner that after the end of the reaction a total amount of 2.5 liters of xylene is distilled oil. The continuously the structural formula of benzodiazepine is also reproduced.

The substances embodying the present invention are basic tricyclic diazepine compounds corresponding to the following general structural formula:

In the above formula R stands for a saturated or unsaturated aiiphatic or cycloaliphatic (hydroaromatic) hydrocarbon radical, or an aryl or aralkyl radical and the phenolic ring of the benzodiazepine compound can be substituted by alkyl and/or alkoxy groups and/or hydroxy groups and/or a halogen.

According to the present invention the novel compounds of the invention are prepared by condensing an unsubstituted or C-substituted o-rtho-phenylene diamine having the formula distilled off xylene removes the alcohol and water formed during condensation. The residual solution is treated at once with active carbon, filtered in hot condition and then cooled. Upon cooling the compound formed crystallizes, is filtered off and washed with ether or a small amount of acetic ester. By concentration of the mother liquor and recrystallization from alcohol 134 grams (72% of the theory) of slightly yellow crystals are ob= tained which are scarcely soluble in benzine ether or water, but can be well crystallized from alcohol, acetic ester, ketones or benzene. The melting point is 182- 184 C.

EXAMPLE 2 In the manner and under the conditions described in the above Example 1, 55 grams of ortho-phenylene diamine in 1 liter of xylene are condensed with grams of 1-ethyl-piperidone-4carboxylic acid-3-ethy1 ester in 1.5 liters of xylene, in such a manner that in the course of 5 hours 2 liters of xylene are distilled oil. The benzo diazepine base thus formed separates by crystallization from the concentrated xylene solution and is then recrystallized from alcohol-acetic ester. The melting point is 139140 C. and the yield amounts to 59% of the theory.

EXAMPLE 3 In the manner and under the conditions described in the above Example 1, 51 grams of ortho-phenylene diamine in 1 liter xylene and 100 grams of l-n-butyl-piperiv done-4-carboxylic acid-3-methyl ester in 2 liters of xylene are condensed in such a manner that in the course of 5 hours 2.5 liters of xylene are distilled off. The com pound formed separates from the residual solution by crystallization and recrystallized from acetic ester. The melting point is 146147 C. and the yield amounts t 61% of the theory.

EXAMPLE 4 3,4- [3 '4'-(1 '-allyl-1 '2'5'6'-tetrahydropyrido) ]-1,5- benzodiazepine- (3) -2-0ne In the manner and under the conditions described access? in the above Example 1, 88 grams of ortho-phenylene diamine in 1 liter of xylene and 171 grams of l-allylpiperidone-4-carboxylic acid-3-ethyl ester in 2 liters of xylene are condensed in such a manner that during the course of the reaction 2.5 liters of xylene are distilled off. The compound thus formed separates from the residual solution by crystallization and is recrystallized from alcohol. The yield amounts to 66% of the theory and the melting point is 144-145 C.

EXAMPLE Under the conditions and in the manner described in the above Example 1, 40 grams of ortho-phenylene diamine in 1 liter of xylene and 93 grams of 1-phenylpiperidonel-carboxylic acid-3-ethyl ester in 2 liters of xylene, are condensed in such a manner that in the course of 4 hours 2 liters of xylene slowly distill over. The compound formed separates from the residual solution by crystallization and is recrystallized from tetrahydronaphthalene. The substance, which is obtained with a yield of 83% of the theory, melts at 248-250 C. with decomposition.

EXAMPLE 6 Under the conditions and in the manner described in the above Example 1, 30 grams of ortho-phenylene diamine in 1 liter of xylene and 78 grams of l-cyclohexylpiperidonel carboxylic acid-3-ethyl ester in 1 liter of xylene are-condensed in-such a-manner that during condensation 1.5 liters of xylene-are-slow-ly distilled ofi. The residual xylene is removed under-slight vacuum and the residue is boiled with acetic ester. The compound-formed separates by crystallization and is recrystallized from acetic ester. The melting point is l27-l28 C. and the yield amounts to 41% of the theory.

EXAMPLE 7 3,4- [3'4'- -benzyl-l '2 '5 '6 '-tetrahydr0pyrid0) JJ ,5 benzodiazepine- (3 -2-0ne Under the reaction conditions and in the'manner described in the above Example 1, '44 grams of orthophenylene diamine in 1 liter of xylene and 100 grams of 1-benzylpiperidone-4-carboxylic 'acid-3-methyl ester in 2 litersof'xylene, are subjected to condensation, whereby atotal'amount of'2.5 liters-of xylene are slowly distilled o'flF. The base separated bycry'stallization from the concentrated xylene solution is recrystallized from isopropanol. The melting point of the base is 165-166 C. and the yield amounts to 75%of'the theory.

3,4 l-3-'-,4'-(-l '-ben"zyl-1 2 5 6 tetr akydropyrido) l7&8)- methyl-I,S-benzOdiaZePine- GSJ 2-one Under the conditions and in the manner describedin the above Example l,"3'8 grams of 3,4-'diamiuo-toluene in 1 liter of xylene are condensed with 70 grams of 1-benzylpiperidone-4-carboxylic acid-3-methylester in 1.5 liters of xylene in such a manner that during condensation 2 liters of xylene are slowly distilled off. The residual xyleneis removed under slight vacuum and the residue is treated with ether. The product formed by crystallization consists of the two expected isomers,which can be separated by crystallization. One isomer-denoted A-which is difiicultly soluble in alcohol, is recrystallized from alcohol. It has a melting point of l29-130 C. and is obtained in a yield of 42% of the theory. The other isomer (denoted B) is easier soluble in alcohol and is recrystallized from dibutyl ether. It melts at 117-118" C. and is obtained in a yield of 13% of the theory.

EXAMPLE 10 Under the reaction and process conditions described in the above Example 1, 63 grams of 4,5 dimethoxy-l,2-diaminobenzene in 1 liter of xylene and 75 grams of l-rnethylpiperidone-4-carboxylic acid-3-methylester in 1 liter of xylene, are condensed, whereby a permanent current of nitrogen is passed through the apparatus and 1.5 liters of xylene are slowly distilled off. The residual xylene is removed under slight vacuum, the residue is boiled with acetic ester and treated with active carbon.

Upon cooling, the desired compound separates from the acetic ester solution by crystallization and is recrystallized from alcohol. It has a melting point of l73-174 C. and is obtained in a yield of 48% of the theory.

EXAMPLE 1.1

Under the reaction and process conditions described in the above Example 1, 37 grams of 4-chloro-orthophenylene diamine in 1 liter of xylene and 75 grams of 1-phenylpiperidone-4-carboxylic acid-3-ethylester in 1 liter of xylene, are condensed in such a manner that during the reaction 1.5 liters of xylene are slowly distilled oif. From the residual xylene solution the desired compound quantitatively separates by crystallization in form of the isomer A. This compound is recrystallized from methyl ethyl ketone. It melts at 219-220 .C. underdecomposition and is obtained in a yield of of the theory.

.Thesecond isomer (isomer B) is obtainedby complete concentration of the above mentioned xylene mother liquor and recrystallization of the residue from methanol. This second isomer has a melting point of 233-235 C. and is obtained in a yield of 8% of the theory.

The compounds embodying the present invention are useful for therapeutic applications, particularly as agents for lowering blood pressure in the human organism, e.g.

by administration per os or by subcutaneous injection.

The compounds embodying the present invention yield wtih organic or inorganic acids salts which are easily soluble in water. For example, .the hydrochloride obtained from the base prepared according to the above Example .1, can be separated from alcohol and has va melting point of 252-254" C. p

it will be understood from the above that'this invention :is not limited to the substances, conditions,proportions and other details specifically described above and can be carried out with'various modifications withoutdeparting from the scope of the invention, as defined in the appended claims. As mentioned above the ,process Lot the invention can be carried out in various. inert organic solvents.

As examples of such inert organic solvents toluene or dibutyl ether-are mentioned. Such solvents can be partly or completely'substituted for xylene in'the above ex amples.

where R is a member of the group consisting of lower alkyl, lower alkenyl, cyclohexyl, phenyl and phenyllower alkyl and W is a member of the group consisting 6 8. A process for preparing a basic, tricyclic diazepine compound of the general formula where R is a member of the group consisting of lower 10 alkyl, lower alkenyl, cyclohexyl, phenyl and phenylof lower alkyl, lower alkoxy, hydroxy, halogen and by- 15 drogen.

2. As a new compound, 3,4-[3'4'-(1'-methyl-1'2'56'- tetrahydropyrido) -1,5-benzodiazepinc-( 3 -2'one.

3. As a new compound, 3,4-[3'4'-(1'-phcnyl-1'2'5'6'- tetrahydropyrido) 1-1 ,5-benzodiazepine-( 3 -2-one.

4. As a new compound, 3,4-[3'4'-(l'-cyclohexyll2'5'6'-tetrahydropyrido)]-1,5-benz0diazepine- (3) 2- one.

5. As a new compound, 3,4-[3'4'-(1-benzyl-1'2'S'6'- tetrahydropyrido)]-7-(8) methyl 1,5 benzodiazepine- (3)-2-one.

6. As a new compound, 3,4-[3'4-(1'-methyl-1'2'5'6'- tetrahydropyrido)]-7,8-dimethoxy- 1,5 benzodiazepine- (3)-2-one.

7. As a new compound, 3,4-[3' '-(l'-phenyl-1'2'S'6'- tetrahydropyrido)]-7-(8) -chloro- 1,5 benzodiazepine- (3)- 2-one.

lower alkyl and W is a member of the group consisting of lower alkyl, lower alkoxy, hydroxy, halogen and hydrogen, which comprises condensing a compound of the formula where W is as above defined, with an N-substituted piperidone'4-carboxylic acid-3-alkyl-cster of the formula CHPGH:

c=o CHa-C-COOR' wherein R has the meaning defined above and R stands for a lower alkyl radical, said condensation being carried out under heating in an inert organic solvent.

9. A process as claimed in claim 8, in which condention is carried out in boiling xylene.

No references cited.

UNITE STATES PATENT UFFTCE esa'mhiewiou os Patent No. 2,928,837 March 15 1960 Rolf Kallischnigg It is hereby certified. that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below) In the heading to the printed specification lines 2 and 3, title of invention for "TETRAHYDROPYRIDO,l 5-BENZODIAZE=- PlNE 2-(3)-ONE" read TETRAHYDROPYRIDO-=1 S BENZODIAZEPINE (3)-2=ONE column l lines 67, to '7l the formula should appear as shown below instead of as in the patent:

column 2 line 17 for "130 read an 150 column 3 second line of the heading of Example 8 for "1. 5=-benzodiazepine 3 (2) -one" read l 5 benzodiazepine-=(3)-2-=0ne o Signed and sealed this 23rd day of May 1961.,

(SEAL) Attest:

ERNEST W, SWIDER DAVID L, LADD Attesting Officer Commissioner of Patents 

1. AS A NEW PRODUCT, A BASIC, TRICYCLIC DIAZEPINE COMPOUND CORRESPONDING TO THE GENERAL FORMULA 